Metallation of beta keto esters



Patented Dec. 25, 1945 2,391,530 METAILATION F BETA KETO ESTES Vernon H. Wallingiord, Ferguson. and must 1!.

Homeyer, St. Louis, Mo., assignorl to Mallinckrodt Chemical Works, St. Louis, 110., a corporation of Milourl No Drawing. Application March 1:, 1941.

Serial No. exam 8, Claims. (Cl. 260-483) This invention relates to the metallation of beta keto esters, and with regard to certain more specific features, to the replacement of active carbon-bonded hydrogen atoms of a wide variety of organic compounds with metals of the class of the alkali and alkaline earth metals.

Thi application is a continuation-in-part of our co-pending application Serial No, 287,000, filed July 28, 1939, Patent No. 2,351,085.

Among the several objects of the invention may be noted the provision of a general process for bringing about a metallation of the type indicated which is characterized in its high yields, its inexpensive and readily procurable reaction materials, and the facility with which it may be carried out. Other objects will be in part obvious and in part pointed out hereinafter. I

The invention accordingly comprises the steps and sequence of steps, and features of synthesis, analysis, or metathesis, which will be exemplified in the processes hereinafter described, and the scope of the application of which will be indicated in the iollowing claims.

Metalorgam'c compounds .01 the types, alkali and-alkaline earth metals, are exceedingly useiul intermediates for the preparation of a wide variety oi organic compounds. Many processes have been devised for the preparation or such compounds, but these prior processes have usually oflered one or another disadvantage, such as low yields, expensive or unavailable reaction ma terials, diiiicult reaction conditions, and the like. The present invention provides a metallation process which, so far as we can determine, is free of all such disadvantages and which consequently is a highly advantageous procedure to use to achieve the desired results.

It is difiicult to define with accuracy the broad class oi materials to which the process oi the present invention applies. In seneral, it appears that the process can be satisiactorily used in all instances where metallation oi the type indicated is wanted. Most of such instances seem to com- Broadly speaking, the oi the present invention comprises treating the-compound to be metallated with a metal alcoholate, preferably.

alcohol-tree, in a reaction medium comprising a dialkyl carbonate. This may be represented by where R and R' are orsanic residue, M isan alkali or alkaline earth metal, R is the radical of the alcoholate, and R" is an alkyl, the CH group being attached to at least two carbon atoms which are multiply bonded to atoms other than carbon.

Whether or not the dialkyl carbonate actually enters into the reaction has not yet been deflnitely established. Its presence appears to be an important factor.

The reaction may be forced to substantial completion by heating, as it progresses, to distill oi! the product alcohol (R'OH in the above equation). In case the original metal alcoholate contains alcohol, such alcohol is likewise removed by this distillation procedure. This procedure. while somewhat optional, is highly advantageous inits improvement of the yield 0! metallocompound obtained.

The iollowing examplesillustrate the present invention, They are exemplary only.

Exurru 1 Ethyl acetoacetate Sodium (11.5 g.) was dissolved in anhydrous.

. sodium ethylate was broken up. Diethyl carprehend thereplacement of an active carbonbonded hydrogen on the organic compound with the metal and the invention will be so described. although it is not intended thereby to so limit the scope of the invention.

Fran the practical standpoint, metallatlon of I the type herein concerned is usually the formation oithe sodium (sodio-) compound. But it will likewise be clearly understood that metallation with the other alkali metals, or the 'alkaline earth metals. is not only ieasible but also expeditious according to the present invention.

'bonate 200 ml.) and ethyl 'acetoacetate g.)

were added and the resulting mixture was stirred until all the sodium ethylate had gone into solution. The reaction flask was connected to a small packed column arranged for distillation under reduced pressure and the metallation reaction was brought to'completlon by heating the reactants at -100 0. and the alcohol ircm the reaction of the sodium ethylate and the acetoacetic ester was removed as distillate at the head oiflie column at 41-43 under mm.

pressure. The metailated ester wasthen isolated by distilling oi! the diethyl carbonate under reduced pressures (150-42 mm.). There remained in the flask 84.3 g. of a slightly oilyand gummy solid. The residual diethyl carbonate and the gummy, oily material present was removed by washing with isopropyl ether. On drying the product under vacuum, a high yield of a white, free-flowing, granular powder was obtained. This was sodio-acetoacetic ester.

To prove further the identity of this sodio derivative, 10.8 g. was added to ice water and acidifled with acetic acid. The liberated oily material was extracted from the aqueous mixture by means of isopropyl ether, and after drying the ether solution the solvent was removed and the residual oil was distilled. A high recovery of ethyl acetoacetate, boiling at 75-765 C. under 18 mm. pressure was obtained.

Exmu: 2

Ethyl a-n-lmtulacetoacetate Diethyl carbonate (150 m1.) and ethyl a-n-butyl- I acetoacetate (62 g.) were added and the resulting mixture stirred until all of the sodium ethylate dissolved. \After connecting the reaction flask to a small packed column, the metallation reaction was brought to completion by heating the reactants at 90-'100 C. until no more alcohol was obtained as distillate at the'head of the column when under 150 mm. pressure.

The presence of a high yield of metallated ethyl a-n-butylacetoacetate was shown by isolating the metallated product in the following manner. The reaction mixture was cooled and the solid material which crystallized out was filtered ofl carefully and ,quickly, washed with isopropyl ether and a portion of it transferred to a flask containing an excess of glacial acetic acid in ice water. The liberated, oily layer was isolated by ether extraction, dried and then distilled. Ethyl a-nbutylacetoacetate was recovered almost quantitatively.

Exlluru 3 Diethyl malonate Sodium ethylate, substantially free of alcohol, was prepared as in Example 1 from sodium metal (6.04 g.) and anhydrous ethyl alcohol (150 ml.). Diethyl carbonate (150 ml.) and diethyl malonate (42 g.) were then added and the mixture was stirred until all of the solid sodium ethylate had gone into solution. The flask was then connected to a small packed column arranged for distillation under reduced pressure. Completion of the metallation reaction was brought about by heating the reactants in the flask at about 90-100 C. and the alcohol from the reaction of the sodium ethylate and diethyl malonate, as well as any small amount left in the sodium ethylate, was removed as distillate at the head of the column at 41-43 C. under 150 mm. pressure.

To further prove the presence of a high yield of metallated diethyl malonate, the contents of the flask were alkylated by refluxing with an excess of isopropyl bromide until the reactants were no longer alkaline to phenolphthalein test paper. The reaction mixture was worked up by adding water, acidifying, extracting with ether, drying the extract, and distilling off the ether. Distillation of the residue gave a yield of 42.6 g. (80.3%) of diethyl isopropylmalonate.- I

I with an excess of isoamyl bromide.

Exmu: 4

Diethyl malonate actants at 100 C. until no more alcohol came of! as distillate at the head of the column. The alcohol was collected for the most part at 41-43 C. under mm. pressure. of alcohol collected was essentially the theoretical amount which would be liberated by the action or two moles of sodium ethylate on one mole of diethyl malonate. This indicated that the dimetallo derivative of diethyl malonate had been formed by this metallation reaction.

The presence of a high yield of the dimetallated derivative of diethyl malonate was shown by alkylating with an excess of ethyl bromide. A good yield of diethyl diethylmalonate was obtained.

Exmrns 5 Diethyl ethylmalonate Sodium ethylate, substantially free of ethyl alcohol, was prepared as in Example 1 from sodium metal (12.1 g.) and anhydrous ethyl alcohol (225 ml.). Diethyl carbonate (300 ml.) and diethyl ethylmalonate (94 g.) were added and the mixture stirred until all of the sodium ethylate had dissolved. After connecting the reaction flask to a small packed column, the metallation reaction was brought to completion by heating the reactants at 90-100 C. until no more alcohol came off as distillate at the head of the column under 150 mm. pressure.

The presence of a high yield of metallated diethyl ethylmalonate was shown by alkylating A yield of 98 g. (76% of theory) of diethyl isoamylethylmalonate was obtained. a

Examtl: 6

Diethyl sec-butulmalonate sodium ethylate had dissolved. After connecting the reaction flask to a small packed column. the metallation reaction was brought to completion by heating the reactants at 90-l00 C. until no more alcohol came oilas distillate at the head of the column under 150 mm. pressure.

The presence of a high yieldof metallated diethyl sec-butylmalonate was shown by alkylating with an excess of ethyl bromide. A yield of 57.8 g. (94.8%) of diethyl sec-butylethylmalonate was obtained.

Previously reported attempts by other methods to prepare the metallated derivative of diethyl sec-butylmalonate and react it with ethyl bromide have given extremely small yields of the desired derivative.-

The total amount asonsso Exams: 7

Dibatul cctylmalonate Potassium n-butylate substantially free of nbutyl alcohol was prepared from potassium (7 g.) and n-butyl alcohol (70 ml.). Di-n-butyl carbonate (175 g.) and di-n-butyl cetylmalonate (753.) 'were added and the mixture was stirred and warmed until, the postassium butylate was dissolved, n-butyl alcohol being simultaneously fractionated out of the refluxing reaction under was stirred until all of thesodium ethy tedis-.

a pressure of 50 mm. Metallation was Judged to be complete when heating the reaction at 90- 100? C. under 50 mm. pressure produced no further n-butyl alcohol at the head of the fractionating column.

The presence of a high yield of metallated clibutyl cetylmalonate was shown by benzylating the reaction mixture with benzyl chloride. A

yield of 60 g. (67%) of di-n-butyl benzylcetylmalonate was obtained, B. P. 283-240 C. at 1 mm., a 1.4712, and F. P. 7 to 11.

The identity of the product was established by converting it successively to the malonic acid;

cetylbenzylacetic acid, the acid chloride, and the 2,4 ,6-tribromoanilide. Cety1benzylacet-(2,4,6-tribronioanilide) melted at 85-87. Analysis: Calculated for Call-14401312: Br 35.0%; found: Br

Diethyl p-methylphenzllmalmmte Sodium ethylate, substantially free or alcohol, was prepared as in Example 1- from sodium metal (2.628.) and anhydrous ethyl alcohol (75 ml.). Diethyl carbonate (100 ml.) and diethyl pmethylphenylmalonate (28.5 g.) were added and the rea' lting mixture stirred until all of the sodium ethylate dissolved. After connecting the reaction flask to a small packed column," the metallation reaction was brought to completion by heating the reactants at 90-100 C. until no more alcohol was obtained as distillate at the head of the column under 150 mm. pressure.

The presence of a high yield of metallated diethyl p-methylphenylmalonate was shown by alkylating with an excess ofethyl bromide. The reaction mixture was worked up in the usual manner and from it was isolated, in good yield,

dlethyl ethyl-p-methylphenylmalonate having a boiling point of lid-117 c. at about 0.5 mm. and an index of refraction of about 72. 1.4912.

Diethyl phenylmalm mte Sodium ethylate, substantially free of ethyl alcohol, was prepared as in Example 1 from 12.1 g.

sodium metal and 225 ml. anhydrous ethyl alcohol. Diethyl carbonate (350 ml.) and diethyl phenylmalonate (118 g.) were added and the mixturestirred until all of the sodium ethylatedissolved. After connecting the reaction flask to a small packed column; the metallatlon reaction was brought to completion by heating the reactants at 90-100- C. until no more alcohol was obtained as distillate at the head of the column under 150 mm, pressure.

The presence of a high yield of metallated diethyl .phenylmalonate was shown by alblating withan excess of ethyl bromide. A yield of 104.3

g. (79%). of diethyl ethylphenylmalonate, boiling at lab-146 C. under 4.5-8 mm. pressure, was obtained.

I 3 Exmu 10 Diethyl phenylmclonatc To diethyl carbonate (450 ml.) was; added solid anhydrous sodium methylate (43 g.) and then diethyl phenylmalonate (177 g.) and the mixture Exams: 11

Ethyl acetoccetate Sodium ethylate, substantially free of was prepared as in Example 1 from 11.5 g. dium metal and 250 m1. anhydrous ethyl alcohol. Diethyl carbonate (250 ml.) and ethyl acetoacee tate g.) were added to the broken up solid and the resulting mixture stirred until all of the sodium ethylate dissolved. After connecting the reaction flask toa small packed column, the I metallation reaction was brought to commotion by heating the reactants at 90-100 0. until no I more alcohol was obtained as distillate at the head of the column under 150 mm. pressure.

The presence of a high yield of metallated ethyl acetoacetate was shown by alkylatlng with an excess of n-hexyl bromide. A yield of 68.7 a. (64.2%) or ethyl -n-hexylaeetoacotate wa -ob- Ethyl acetoacetate Sodium ethylate, substantiall free of alcohol, was prepared as in Example 1 from sodium metal (23 g.) and anhydrous ethyl alcohol (5001 111.). Diethyl carbonate (300 ml.) and ethyl acetoacetate g.) were added to the broken 1195011! and the resulting mixture stirred until" all of the sodium ethylate dissolved. Alter connecting the reaction flask to a small p cked column the metallation reactionwas brought to completion by heating the reactants at %100 C. until .no more alcohol was obtained as distillate at the head of the column under 150 mm. pressure. The alcohol was collected for the most part at 41-42 C., and from its weight and refractive index it was found that 1 mole of alcohol had been liberated for each mole of sodium used. This indicated that the reaction had taken place to form the di-metallo derivative of ethyl acetoacetate in practically quantitative yield.

The presence of a high yield of the metallated ethyl acetoacetate was further shown by alkylating with an excess of ethyl bromide. A good yield of ethyl a,u-diethyl acetoacetate wu obtained.

I Exsxru: 13

Ethyl a-n-butylacetoacetate A diethyl carbonate solution of the. mctallated derivative of ethyl a-n-butylacetoacetate was prepared as described in paragraph one of Example 2 above from sodium metal (7.66 .g.), anehydrous ethyl alcohol ml), dlethyl' carbonate ml.) and ethyl 'u-n-butylacetoocetate The presence ot-a high yield of metallated ethyl a-n-butylacetoacetate wasshown by alkyl- ,ating with an excess of n-butylbromide.- A good yield of ethyl a,a-di-n-butylac etoacetate was obtained. I

Exam? 14 n-Butyl benaoylacetate Potassium butylate, substantially free or alcohol, was prepared by the method described in Example 1 for the preparation of sodium ethylate, by dissolving potassium (12.45 g.) in n-butyl alcohol (150 ml.) and then removing the excess alcohol .indervacuum, Di-n-butyl carbonate (160 ml.) and n-butyl benzoylacetate (70 g.) were added and the resulting mixture stirred until all oithe potassium butylate was dissolved. After connecting the reaction flask to a small packed column, the metallation reaction was brought to completion by heating the reactants at 90-100 C. until no more n-butyl alcohol was ,obtained as distillate at the head of the column under 150 mm. pressure. p

The presence of a high yield of metallated n-butyi benzoylacetate was shown by alkylating with an excess of ethyl bromide. A good yield of n-butyl. ethylbenzoylacetate was obtained. The boiling point oi the ester was about 116-117" C. at 1 mm., and its refractive index was about a 1.5003.

- Exauru: 15

I "n-Pro'pul fl-ketononanoate Potassium propylate, substantially free of alcohol, was prepared by the method described in Example 1 for the preparation of sodium ethylate, by dissolvingpotassium metal (6.81 g.) in anhydrous n-propyl alcohol (100 ml.) and then removing the excess alcohol under vacuum, Di-

n-propyl carbonate (75 ml.) and n-propyl fi-ketononanoate (37.25 g.) were added and the resuiting mixture stirred until all of the potassium propylate had dissolved. After connecting the reaction flask to a small packed column the metallation reaction-was brought to completion by heating the reactants at 90100 C. until no more alcohol Was obtained as distillate at the head oi? the column under 150 mm. pressure.

The presence of a high yield of -metallated n-propyl fi-ketononanoate was shown by alkylat- Qing with an excess of ethyl bromide. A good yield of n-propyl a-ethyl p-ketononanoate was isolated. The boiling point of the ester was about 103-105 C. at about 1-2 mm. pressure. The index of refraction was about n 1.4355,

EXAMPLE 16 Ethyl a-cycno-p-methulphenylacetate Sodium ethylate, substantially free of alcohol, was prepared as in Example 1 from sodium metal (3.74 g.) and anhydrous ethyl alcohol (75 ml.). Diethyl carbonate (100 ml.) and ethyl a-OYfi-IIO- p-methylphenylacetate (33 g.) were added and theresulting mixture stirred until all of the sodium ethylate dissolved. After connecting the reaction flask to a small packed column, the metallation reaction was brought to completion by heating the reactants at 90100 C. until no more 'alcohol was obtained as distillate at the head of the column under 150 mm. pressure.

The presence of a high yield of metallated ethyl a-cyano-p-methylphenylacetate was shown by alkylating with an'excess of ethyl bromide. A good 'yield of ethyl a-cyano a-ethyl p-methyl-phenylacetate. having a boiling point 01 104-108 C.at

about 2.5 mm. and a refractive index of about 11 1.4985 was obtained.

Examn: 17

n-Propul a-cyanoisocaproate Sodium propylate, substantially free of alcohol, was prepared by the method described in Example 1 for the preparation of sodium ethylate, by dissolving sodium (5.0 g.) in anhydrous n-propyl alcohol (100 m1.) and then removing the excess alcohol under vacuum. Di-n-propyl carbonate ml.) and n-propyl a-cyano-isocaproate (39.5 g.) were added and the resulting mixture stirred until all of the sodium propylate was dissolved. After connecting the small reaction flask to a small column, the metallation reaction was brought to completion by heating the reactants at -100 C. until no more n-propyl alcohol was obtained as distillate at the head of the column under mm. pressure.

The presence of a high yield of metallated n-propyl c-cyanoisocaproate was shown by alvkylating with an excess of ethyl bromide. A high yield of n-propyl a-cyano-c-ethylisocaproate was obtained. The boiling point of the ester was 65.5- 69 C. at 0.4 to 0.9 mm. pressure. Theindex of refraction of the ester was about 11 1.4299.

EXAMPLE 18 Diethyl malonate -the resulting mixture was stirred until all of the magnesium ethylate had gone into solution. The reaction flask was then connected to a small packed column arranged for distillation under reduced pressure and the metallation reaction was brought to completion by heating the reactants at 90-110 C. and the alcohol from the reaction was simultaneously removed as distillate at the head of the column at 41-43 C. under 150 mm. pressure. The metallated ester was then isolated by removing one-fourth of the diethyl carbonate solution, distilling 011 the diethyl carbonate under reduced pressure (150 mm.) and allowing the residue to cool and solidify. There remained in the flask a wax-like, gummy solid.

To prove further the identity of this magnesio derivative, the wax-like gummy solid obtained above was treated with cold water and acldifled with hydrochloric acid. The liberated oily material was extracted from the aqueous mixture 'by means of isopropyl ether, and after drying the ether solution, the solvent was removed and the residual oil was distilled. A high recovery 01' di- 'consisted of a mixture of diethyl ethylmalonate and diethyl diethylmalonate.

Magnesium turning (6.0 g.), catalyzed with mercuric chloride (1.5 g.), were dissolved in anhydrous ethyl alcohol (200 ml.) by refluxing 24 hours. Diethyl carbonate (300 ml.) and diethyl ethylmalonate (47 g.) were then added and the resulting mixture was stirred until all of the magnesium ethylate had gone into solution. The flask was then connected to a small packed column arranged for distillation under reducedpressure. Completion of the metallation reaction was brought about by heating the reactants in the flask at about 90-100 0. and the alcohol from the reaction of the magnesium ethyl/ate and diethyl ethylmalonate, as well as that left in the magnesium ethylate, was removed as distillate at the head of the'column at 41-43 C. under 150 mm. pressure.

To prove the presence of a high yield ofmetal- Iated diethyl ethylmalonate, one-halt oi the contents of the flask was aikylated by refluxing 24 hours with an excess'oi ethyl iodide. The reaction mixture was worked up by adding water, acidifyin extracting with ether, drying the extract. and distilling on the ether and diethyl carbonate. Fractionation of the residue gave a yield of 22.3 g. (82.6%) oi! diethyl diethyimalonate.

To further prove the presence of a high yield of metallated diethyl ethylmalonate, one-fourth oi the original reaction mixture was placed in a flask and all of the diethyl carbonate was removed under reduced pressure (150 mm.). On cooling, there remained in the flask a brown, bummy, wax-like solid. On adding water, acidifying, extracting with ether, drying the extract, and distilling off the ether and iractionating the residual oil, a high yield of unchanged diethyl ethylmalonate was obtained.

Carrying out the above metallation procedures without the simultaneous removal, by distillation, of the alcohol produced in the reaction, is entirely feasible, but the yield is decreased from that otherwise obtainable.

Attention is directed to our copending applications Serial No. 594,372, flled May 17, 1945, Serial N0. 625,449, flled October 29, 1945, and

Serial No. 625,450, filed October 29, 1945.

In view of theabove, it will be seen that the several objects of the invention are achieved and other advantageous results attained.

As many changes could be made in the above.

aconnsooex where R is a hydrocarbon radical selected from the group consisting oi aromatic and saturated aliphatic hydrocarbon radicals, and Y is an alkyl radical, which comprises reacting the ester with an anhydrous alcoholate oi a metal selected from the group consisting of sodium, potassium and magnesium, in a reaction medium consisting essentially of a dialkyl carbonate, and removing alcohol.

2. The method of metallating a fl-keto ester of the following structure:

R.CO.CH2.CO2Y

'where R is a hydrocarbon radical selected from the group consisting of aromatic and saturated aliphatic hydrocarbon radicals, and Y is an alkyl radical, which comprises reacting the ester with an anhydrous alcoholate ofa metal selected from the group .consisting of sodium, potassium and magnesium, in a reaction medium consisting essentially of a dialkyl carbonate, and subjecting the mixture to distillation for removing alcohol therefrom.

3. The method of metallating ethyl acetoacetate which comprises reacting the ester with anhydrous sodium ethylate in a reaction medium consisting essentially of diethyl carbonate, and removing alcohol.

4. The method of metallating n-propyl p-ketoester with anhydrous alcohol-ire sodium ethylate,

, ing.alcohol.

8. The method 01' metallating n-butyl benzoylin a reaction medium consisting essentially of dlethyl carbonate, and continuously subjecting the mixture to distillation for removing alcohol.

7. The method of metallating n-propyl p-ketononanoate, which comprises mixing andheatinz the ester with anhydrous alcohol-tree potassium propylate, in a reaction medium consisting essentially oi di-n-propyl carbonate, and continuously subjecting themixture to distillation for removacetate which comprises mixing and heating the ester with anhydrous alcohol-tree potassium butylate, in a reaction medium consisting essentially of di-n-butyl carbonate, and continuously subjecting the mixture to distillation for remov- 1118 alcohol. j

VERNON H. WAILINGFORD.

AUGUST 8. HOMEYER. 

